Anise flavored medication

ABSTRACT

An anise flavored liquid medication. The liquid medication contains phenylephrine and an anethole analog that is substantially free of aldehyde groups. In one example, the anethole analog can be 1-methoxy-4-n-propylbenzene.

FIELD OF THE INVENTION

The present invention is directed towards medication, more particularlyanise flavored liquid medication that comprises phenylephrinehydrochloride.

BACKGROUND OF THE INVENTION

Flavors are commonly added to liquid medications to mask the unpleasanttaste that many actives have. Anise flavoring has been widely used inliquid medications, in particular nighttime multi-symptom relief (MSR)cold/flu medications. Many consumers enjoy, trust, and expect thisflavor.

Some consumers would like an anise flavored MSR cold/flu medication thatalso contains phenylephrine hydrochloride (PE), a decongestant. However,this formulation is not currently sold because it has surprisingly beenfound that anise flavoring comprising trans-anethole causes PE todegrade, which makes the liquid medication less effective andsignificantly reduces the shelf life of the product.

Therefore, there is a need for an anise flavored liquid medication thatcomprises PE and where the composition has a shelf life of at least 18months.

SUMMARY OF THE INVENTION

An anise flavored liquid medication comprising: (a) phenylephrine; and(b) an anethole analog that is substantially free of aldehyde groups.

A dose of an anise flavored liquid medication comprising: (a) 650 mgacetaminophen; (b) 20 mg dextromethorphan; (c) 12.5 mg doxylaminesuccinate; (d) 10 mg phenylephrine hydrochloride; and (e) an anetholeanalog.

BRIEF DESCRIPTION OF THE DRAWINGS

While the specification concludes with claims particularly pointing outand distinctly claiming the subject matter of the present invention, itis believed that the invention can be more readily understood from thefollowing description taken in connection with the accompanyingdrawings, in which:

FIG. 1 shows a proposed mechanism for trans-anethole to degrade to formtwo aldehydes;

FIG. 2A shows the chemical structure of trans-anethole (CAS #104-45-0);

FIG. 2B shows the chemical structure of 1-methoxy-4-n-propylbenzene; and

FIG. 3 shows the predicted percentage of PE loss after six months at 40°C., of thirteen different examples, as determined by the AFRICAStability Test Method.

DETAILED DESCRIPTION OF THE INVENTION

Flavoring is frequently added to liquid medications to mask theunpleasant taste of some actives. Anise flavoring has been widely usedin liquid medications.

Currently, anise flavoring cannot be formulated with PE because the PEdegrades. The inventors surprisingly found that trans-anethole, which iscommonly found in anise flavoring, causes PE to degrade. Therefore, itwas necessary to find a compound that tastes similar to anise that doesnot cause PE degradation. Furthermore, the PE stability must be balancedwith a formulation with the desired taste and if present, the stabilityof other actives.

It is known that aldehydes, which are frequently found in flavoring, inparticular cherry flavoring, cause PE degradation in liquid medications.Phenylephrine degradation in the presence of aldehydes is described inU.S. patent application Ser. No. 11/408,299. However, it wassurprisingly found that formulations comprising trans-anethole showedaccelerated degradation of phenylephrine. While not wishing to be boundby theory, it is believed that the trans-anethole degrades to form twoPE-reactive aldehydes, anisaldehyde and acetaldehyde, as illustrated inFIG. 1.

Since trans-anethole causes PE loss in liquid medication, it wasnecessary to find a compound that has similar properties totrans-anethole, in particular a similar aroma and taste profile, butdoes not cause PE to degrade over time. The compound also needed toprovide a shelf life of at least eighteen months. It was surprisinglyfound that an analog of trans-anethole that is substantially free ofaldehyde groups can have a similar taste and aroma profile and give thedesired shelf life. This was surprising because although the analog ischemically similar to trans-anethole, structural analogs are notnecessarily functional analogs and can frequently have very differentphysical, chemical, biochemical, or pharmacological properties.

Non-limiting examples of anethole analogs can include1-methoxy-4-n-propylbenzene, methyl anisate, anisole, 2-chloroanethole,2,6-dichloroanethole, 3-nitroanethole, 3,5-dinitroanethole,3-cyanoanethole, 3,5-dicyanoanethole, 1-methoxy-3-(1-propenyl)benzene,and combinations thereof.

In one example, the anethole analog is 1-methoxy-4-n-propylbenzene(dihydroanethole). When the concentration of dihydroanethole wasadjusted to take into account the analog's unique properties, such asits propensity to have a lower aroma and taste threshold, and, a lesssweet, drier, almost woody aftertaste than trans-anethole, it wassurprisingly found that dihydroanethole was an acceptable substitute fortrans-anethole. In one example, additional flavor ingredients can beadded to modify the overall sensory experience as desired.

FIG. 2 compares the structures of FIG. 2A, trans-anethole, and FIG. 2B,the anethole analog dihydroanethole. Trans-anethole has a carbon chainwith a double bond, which is the proposed source of aldehyde formationvia the mechanism in FIG. 1. However, dihydroanethole does not have thisdouble bond and therefore does not break down to form aldehydes.

The present invention uses an anethole analog in the formulation of amedicament that comprises PE and tastes like anise.

As used herein, “dose” refers to a volume of liquid medicationcontaining an amount of a drug active suitable for administration on asingle occasion, according to sound medical practice. A dose can beorally administered and is typically swallowed immediately. In oneexample, a dose can be about 30 mL, in another example about 25 mL, inanother example about 20 mL, in another example about 15 mL, and inanother example about 10 mL. The concentration of active ingredients canbe adjusted to provide the proper doses of actives given the liquid dosesize

As used herein, “medication” refers to medications, such aspharmaceuticals, including prescription medications and/orover-the-counter medications. In some examples, a medication can be asupplement.

As used herein, “shelf life” refers to the length of time a liquidmedication is given following manufacture before it is consideredunsuitable for sale or consumption. A liquid medication comprising PE isconsidered unsuitable for sale when the PE concentration is 10% lowerthan the level claimed on the label. In one example, the shelf life isgreater than about 6 months, in another example greater than about 12months, in another example greater than about 18 months, and anotherexample greater than about 24 months, in another example greater thanabout 30 months, and in another example greater than about 36 months.Shelf life can be determined by performing the Accelerated StabilityTest Method, described hereafter. If no significant change inconcentration of the actives is found during the three-month period ofthe Acceleratred Stability Test, then the product can be typicallyplaced in the market with a shelf-life of up to two years. For apharmaceutical product a “significant change” is defined by theInternational Conference on Harmonization (ICH) as a 5% change inconcentration from its initial value at t=0.

Since consumers generally suffer from a few colds per year, it isimportant that the cold products have a shelf life that allows them toused for multiple colds. When consumers are feeling sick, they do notwant to purchase more products because theirs has expired. Furthermore,a longer shelf life gives the store more time to sell the product. Somestores will not sell a pharmaceutical product where the product willexpire within twelve months, since that is not acceptable to consumers.Therefore, products that have greater stability are more advantageous.

In one example, the mean loss of PE concentration is less than about6.5% within a 95% confidence interval over 6 months according to theAccelerated Stability Test Method, described hereafter, in anotherexample less than about 6% within a 95% confidence interval, in anotherexample less than about 5.5% within a 95% confidence interval, inanother example less than about 5% within a 95% confidence interval, inanother example about 4.5% within a 95% confidence interval, in anotherexample less than about 4% within a 95% confidence interval, and inanother example less than about 3.5% within a 95% confidence interval.

FIG. 3 shows the predicted percentage of PE loss after six months at 40°C., 75% relative humidity. The twelve examples that were tested in FIG.1 were tested using the AFRICA Stability Test Method, describedhereafter. The twelve examples correspond to Examples 1-12, describedhereafter. Examples 7, 8, and 9 have the best PE stability and theseformulations could be used in compositions that have a shelf life of atleast two years.

FIG. 3 shows that that Example 1, a formulation comprising aniseflavoring, which comprises many flavoring components includingtrans-anethole, and Example 2, a formulation comprising trans-anetholeand no other flavoring components, have the most PE degradation.Furthermore, the PE degradation for both Example 1 and 2 isstatistically the same. This observation led the inventors to determinethat trans-anethole was primarily responsible for the PE degradation.The PE loss that was observed in Examples 1 and 2 is too high and theshelf life would be significantly shorter than 24 months.

Example 3, which had no flavoring component, was tested and it hadsignificantly less PE degradation than Examples 1 and 2. Thisobservation further confirmed that a significant amount of PEdegradation is from the anise flavoring, in particular thetrans-anethole.

Examples 4, 5, and 6 all had varying amounts of the anethole analogdihydroanethole. Example 4 had the least amount of PE loss and betweenExamples 4, 5, and 6, and is the most commercially desirable from astability perspective. However, Examples 4, 5, and 6 are not the mostdesirable from a taste perspective, since dihydroanethole has a strongertaste than trans-anethole.

Examples 7, 8, and 9 all have 0.00025% (2.5 ppm) dihydroanethole andvarying amounts of xanthan gum. Xanthan gum is a thickener and thereforecompositions that comprise more xanthan gum will have a greaterviscosity. It has been found that 0.00025% (2.5 ppm) dihydroanethole canprovide the desired level of anise flavor. There is no statisticaldifference between the stability in Examples 7, 8, and 9 and therefore,the amount of xanthan gum in the composition did not impact thestability of the PE. All three examples have less than 5% PE loss andcould be marketed with a shelf life of at least about two years.

Examples 10, 11, and 12 have varying amounts of anise flavoringcomprising trans-anethole. These examples show that even Example 10,which has 25% of the anise flavoring with trans-anethole of Example 1,can cause significant PE loss. The PE loss that was observed in Examples10, 11, and 12 is too high and the shelf life would be significantlyshorter than 24 months.

Examples 13 and 14 compare two formulas, one without ethanol (Example13) and another with 7.25% of 95% ethanol (Example 14). Ethanol canprovide superior sensory benefits and can also help with the solubilityof the anethole analog, as well as other flavoring components, andactives in the solution. Ethanol can also be desirable in a liquidmedication that is intended for nighttime use. In one example, thecomposition comprises 3% to 15% ethanol, in another example 4% to 12%ethanol, in another example 5% to 9% ethanol, and in another example 6%to 8% ethanol.

The stability of PE must also be balanced with a consumer acceptabletaste. Some consumers prefer a composition that has a subtle impressionof anise flavor. Some consumers also prefer a slightly medicinal taste.It has been found that it is difficult for consumers to notice the aniseflavor if it is too low. However, if the dihydroanethole is too high,consumers complain that the formulation tastes too medicinal and someconsumers complain that the formulation tastes like diesel fuel. Inanother example, the liquid medication comprises from about 1 ppm toabout 50 ppm anethole analog, in another example from about 1 ppm toabout 40 ppm anethole analog, in another example from about 1 ppm toabout 30 ppm anethole analog, in another example from about 1 ppm toabout 20 ppm anethole analog, in another example from about 1 ppm toabout 10 ppm anethole analog, and in another example from about 1 ppm toabout 5 ppm anethole analog. In one example, the liquid medication hasfrom about 1 ppm to about 10 ppm dihydroanethole, in another examplefrom about 1.5 ppm to about 7 ppm dihydroanethole, and in anotherexample about 2 ppm to about 5 ppm dihydroanethole. In one example, theliquid medication comprises about 3 ppm dihydroanethole. Lessdihydroanethole can be used than anise flavoring that containstrans-anethole because dihydroanethole has a stronger flavor thantrans-anethole.

In one example, the liquid pharmaceutical composition comprises notrans-anethole, in another example the composition comprises less thanabout 0.001% trans-anethole, in another example the compositioncomprises less than about 0.01% trans-anethole, and in another examplethe composition comprises less than about 0.025% trans-anethole.

pH can also impact the stability of the liquid medication. A lower pHcan increase the amount of APAP that degrades as the medication ages.When APAP ages, it not only becomes less effective, it also makes thesolution slightly brown, which is not acceptable to consumers.

However, PE is more stable at a lower pH. Therefore, the pH must bebalanced so APAP and PE are both stable. In one example, the liquidmedication has a pH of about 2 to about 6, in another example from about3 to about 5.75, in another example from about 3.5 to about 5.5, inanother example from about 3.75 to about 5.25, and in another examplefrom about 4 to about 5.

In one example, the liquid medication can comprise from 0.005% to 0.5%PE, in another example 0.01% to 0.1% PE, and in another example 0.02% to0.04% PE. In one example the liquid medication can comprise 5 mg PE perdose, in another example 10 mg PE per dose, and in another example 20 mgPE per dose.

A dose of liquid medication can be from about 10 mL to about 75 mL, inanother example from about 15 mL to about 50 mL, in another example fromabout 25 mL to about 40 mL, and in another example from about 28 mL toabout 35 mL. In one example, a dose of the liquid medication is about 30mL, in another example about 20 mL, and in another example about 15 mL.In one example, the dose is intended to be administered every 4 hours,in another example every 6 hours, in another example every 8 hours, andin another example every 12 hours.

In addition to comprising PE, the liquid compositions can comprise oneor more drug actives in addition to PE. In one example, the drug activescan be immediate release drug actives, extended release drug actives, ordelayed release drug actives. In one example, the additional drug activecan be formulated as particles and in another example the active can beformulated as coated beads.

In one example, the additional drug active is a MSR cold/flu activewhich can be used to treat one or more cold/flu symptoms. MSR cold/fluactives can be used to treat a variety of cold/flu symptoms includingnasal congestion, runny nose, sneezing, headache, dry cough, sorethroat, sinus pressure or pain, chest congestion, muscle aches/pains,wet/chesty cough, fever, and combinations thereof. MSR cold/flu activescan include decongestants, expectorants, antihistamines, antitussives,pain relievers, and combinations thereof.

In one example, MSR cold/flu actives can be formulated for daytime useor nighttime use. In one example, the liquid medication comprisesinstructions that direct a user to ingest the medication at night beforebedtime.

Non-limiting examples of expectorants can include guaifenesin, ambroxol,bromhexine, and combinations thereof. In one example, the expectorantcan be guaifenesin. In one example a dose can comprise 200 mg ofguaifenesin and in another example 400 mg of guaifenesin.

Non-limiting examples of antihistamines can include chlorpheniramine,desloratadine, levocetirizine, diphenhydramine, doxylamine succinate,triprolidine, clemastine, pheniramine, brompheniramine,dexbrompheniramine, loratadine, cetirizine and fexofenadine, amlexanox,alkylamine derivatives, cromolyn, acrivastine, ibudilast, bamipine,ketotifen, nedocromil, omalizumab, dimethindene, oxatomide, pemirolast,pyrrobutamine, pentigetide, thenaldine, picumast, tolpropamine,ramatroban, repirinast, suplatast tosylate aminoalkylethers, tazanolast,bromodiphenhydramine, tranilast, carbinoxamine, traxanox,chlorphenoxamine, diphenylpyaline, embramine, p-methyldiphenhydramine,moxastine, orphenadrine, phenyltoloxamine, setastine, ethylenediaminederivatives, chloropyramine, chlorothen, methapyrilene, pyrilamine,talastine, thenyldiamine, thonzylamine hydrochloride, tripelennamine,piperazines, chlorcyclizine, clocinizine, homochlorcyclizine,hydroxyzine, tricyclics, phenothiazines, mequitazine, promethazine,thiazinamium methylsulfate, azatadine, cyproheptadine, deptropine,desloratadine, isothipendyl, olopatadine, rupatadine, antazoline,astemizole, azelastine, bepotastine, clemizole, ebastine, emedastine,epinastine, levocabastine, mebhydroline, mizolastine, phenindamine,terfenadine, tritoqualine, and combinations thereof.

In one example the liquid composition can comprise from about 0.01% toabout 0.1% antihistamine, in another example from about 0.02% to about0.07% antihistamine, and in another example from about 0.03% to about0.05% antihistamine. In one example, the antihistamine can be doxylaminesuccinate and a dose of liquid medication can comprise 12.5 mgdoxylamine succinate. In another example, the antihistamine can bechlorpheniramine. In one example a dose can comprise 2 mg ofchlorpheniramine and in another example a dose can comprise 4 mg ofchlorpheniramine.

Non-limiting examples of antitussives can include dextromethorphan HBr(DXM), codeine, chlophedianol, levodropropizine, and combinationsthereof. In one example the liquid medication can comprise from about0.01% to about 0.2% antitussive, in another example from about 0.025% toabout 0.1%, and in another example from about 0.04% to about 0.075%antitussive. In one example the antitussive can be selected from thegroup consisting of DXM, chlophedianol, and combinations thereof. In oneexample a dose can comprise 15 mg DXM, in another example 20 mg DXM, andin another example 30 mg DXM. In another example a dose can comprise12.5 mg chlophedianol.

Non-limiting examples of pain relievers can include APAP, ibuprofen,ketoprofen, diclofenac, naproxen, aspirin, and combinations thereof. Inone example the liquid medication can comprise from about 0.5% to about3.5% pain reliever, in another example from about 1% to about 3% painreliever, and in another example from about 1.5% to about 2% painreliever. In one example the pain relievers can include APAP, ibuprofen,naproxen, or combinations thereof. In one example a dose can comprise325 mg to 500 mg APAP, in another example 200 mg ibuprofen, and inanother example, 200 mg naproxen.

In one example, the cold/flu dosage unit can further comprise astimulant such as caffeine.

In one example, the dosage units can comprise one or more MSR cold/fluactives, in another example two or more MSR cold/flu actives, in anotherexample three or more MSR cold/flu actives, and in another example fouror more MSR cold/flu actives. In one example, the dosage unit cancomprise exactly one MSR cold/flu active, in another example exactly twoMSR cold/flu actives, in another example exactly three MSR cold/fluactives, and in another example exactly four MSR cold/flu actives. Inone example the dosage units can comprise APAP, doxylamine succinate,DXM, and PE.

The compositions can comprise a sweetener to provide sweetness and tastemasking of the PE as well as any additional actives that may be present.In one example, the composition comprises from about 2% to 25%sweetener, in another example from about 5% to 20% sweetener, in anotherexample from about 7% to 15% sweetener, and in another example fromabout 8% to 12% sweetener. Non-limiting examples of sweeteners caninclude nutritive sweeteners, sugar alcohols, synthetic sugars, highintensity natural sweeteners, and combinations thereof.

Non-limiting examples of nutritive sweeteners can include fructose,galactose, and combinations thereof.

In one example, the liquid composition does not comprise glucose becauseglucose is an aldehyde. In another example, the liquid composition doesnot comprise sucrose, including liquid sucrose, because sucrose canhydrolyze to its constituent sugars, namely glucose and fructose. Inanother example, the liquid compositions do not comprise high fructosecorn syrup.

Non-limiting examples of sugar alcohols can include xylitol, sorbitol,mannitol, maltitol, lactitol, isomalt, erthritol, glycerin, andcombinations thereof. In one example the composition can comprise fromabout 1% to about 30% sugar alcohol, in another example from about 5% toabout 28% sugar alcohol, in another example about 10% to about 25% sugaralcohol, and in another example about 15% to about 23% sugar alcohol. Inone example the composition comprises from about 5% to about 20%sorbitol, in another example from about 7% to about 18% sorbitol, and inanother example from about 10% to about 15% sorbitol. In anotherexample, the composition comprises from about 3% to about 15% glycerin,in another example from about 5% to about 10% glycerin, and in anotherexample from about 7% to about 9% glycerin.

Non-limiting examples of synthetic sweeteners can include sodiumsaccharin, acesulfame potassium, sucralose, aspartame, monoammoniumglycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotame,cyclamates, and mixtures thereof. In one example the composition cancomprise from about 0.01% to about 0.5% artificial sweetener, in anotherexample from about 0.1% to about 0.3% artificial sweetener, and inanother example about 0.15% to about 0.25% artificial sweetener.

Non-limiting examples of high intensity natural sweeteners can includeneohesperidin dihydrochalcone, stevioside, rebaudioside A, rebaudiosideC, dulcoside, monoammonium glycyrrhizinate, thaumatin, and combinationsthereof.

The present liquid components typically comprise a solvent. A solventcan be used to dissolve the anethole analog, phenylephrine and/or otheractive(s) into solution.

Non-limiting examples of solvents can include water, propylene glycol,ethanol, and mixtures thereof. In one example the composition comprisesfrom about 60% to about 95% solvent, in another example from about 70%to about 90% solvent, and in another example from about 80% to about 88%solvent.

In one example, the composition comprises water and propylene glycol. Inone example, the composition comprises from about 35% to about 75%water, in another example from about 40% to about 65% water, in anotherexample from about 45% to about 60% water, and in another example fromabout 48% to about 56% water. In another example, the composition cancomprise from about 10% to about 35% propylene glycol, in anotherexample from about 15% to about 30% propylene glycol, and in anotherexample from about 20% to about 25% propylene glycol.

In one example, the composition comprises a buffer. The buffer can helpmaintain a constant pH within the liquid composition. In one example theliquid composition comprises from about 0.05% to about 2% buffer, inanother example from about 0.1% to about 1% buffer, in another examplefrom about 0.15% to about 0.5% buffer, and in another example from about0.18% to about 0.25% buffer. Buffers can include acetate buffers,citrate buffers, and phosphate buffers. Non-limiting examples of bufferscan include acetic acid, sodium acetate, citric acid, sodium citrate,monobasic sodium phosphate, dibasic sodium phosphate, sodium carbonate,sodium bicarbonate, succinic acid, sodium succinate, potassiumdihydrogen phosphate, and phosphoric acid.

In one example, the composition comprises a preservative. In one examplethe liquid composition comprises from about 0.01% to about 1%preservative, in another example from about 0.05% to about 0.5%preservative, in another example from about 0.07% to about 0.3%preservative, and in another example from about 0.08% to about 0.15%preservative. Non-limiting examples of preservatives can includebenzalkonium chloride, ethylenediaminetetraacetic acid (EDTA), benzylalcohol, potassium sorbate, parabens, benzoic acid, sodium benzoate, andmixtures thereof.

In one example, the composition comprises a thickener. In one examplethe liquid composition comprises from 0.01% to 3% thickener, in anotherexample 0.05% to 1.5% thickener, in another example 0.1% to 0.75%thickener, and in another example 0.12% to 0.3% thickener. Non-limitingexamples of thickeners can include xanthan gum, carrageenan, polyacrylicacid, polyvinylpyrrolidone, cellulosic polymers includingcarboxymethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose,and hydroxypropylmethylcellulose, and combinations thereof.

The liquid composition can optionally include one or more sensates.Non-limiting examples of sensates can include cooling sensates, warmingsensates, tingling sensates, and combinations thereof. Sensates canuseful to deliver signals to the user.

Non-limiting examples of cooling sensates can include WS-23(2-Isopropyl-N,2,3-trimethylbutyramide), WS-3(N-Ethyl-p-menthane-3-carboxamide), WS-30(1-glyceryl-p-mentane-3-carboxylate), WS-4(ethyleneglycol-p-methane-3-carboxylate), WS-14(N-t-butyl-p-menthane-3-carboxamide), WS-12(N-(4-,ethoxyphenyl)-p-menthane-3-carboxamide), WS-5(Ethyl-3-(p-menthane-3-carboxamido)acetate, Menthone glycerol ketal(sold as Frescolat® MGA by Haarmann & Reimer), (−)-Menthyl lactate (soldas Frescolat® ML by Haarmann & Reimer), (−)-Menthoxypropane-1,2-diol(sold as Coolant Agent 10 by Takasago International),3-(1-menthoxy)propane-1,2-diol, 3-(1-Menthoxy)-2-methylpropane-1,2-diol,(−)-Isopulegol is sold under the name “Coolact P®” by TakasagoInternational, cis & trans p-Menthane-3,8-diols(PMD38)—TakasagoInternational, Questice® (menthyl pyrrolidone carboxylate),(1R,3R,4S)-3-menthyl-3,6-dioxaheptanoate—Firmenich, (1R,2S,5R)-3-menthylmethoxyacetate—Firmenich, (1R,2S,5R)-3-menthyl3,6,9-trioxadecanoate—Firmenich, (1R,2S,5R)-menthyl11-hydroxy-3,6,9-trioxaundecanoate—Firmenich, (1R,2S,5R)-3-menthyl(2-hydroxyethoxy)acetate—Firmenich, Cubebol—Firmenich, Icilin also knownas AG-3-5, chemical name1-[2-hydroxyphenyl]-4-[2-nitrophenyl-]-1,2,3,6-tetrahydropyrimidine-2-one),4-methyl-3-(1-pyrrolidinyl)-2[5H]-furanone, Frescolat ML—menthyllactate, Frescolat MGA—menthone glycerin acetal, Peppermint oil,L-Monomenthyl succinate, L-monomenthyl glutarate,3-1-menthoxypropane-1,2-diol—(Coolact 10), 2-1-menthoxyethanol (Cooltact5), TK10 Coolact (3-1-Menthoxy propane-1,2-diol), Evercool™ 180(N-(4-cyanomethylphenyl)-ρ-menthanecarboxamide)), and combinationsthereof. In one example, the composition can comprise from about 0.005%to about 1% cooling sensate, in another example from about 0.05% toabout 0.5% cooling sensate, and in another example from about 0.01% toabout 0.25% cooling sensate.

In one example, the cooling sensate can be EverCool™ 180 (available fromGivaudan of Cincinnati, Ohio, as a 5% solution ofN-(4-cyanomethylphenyl)-ρ-menthanecarboxamide in a flavoring ingredientcool white grape, or as a 7.5% solution ofN-(4-cyanomethylphenyl)-ρ-menthanecarboxamide in a flavor ingredientsuch as spearmint or peppermint.

Non-limiting examples of warming sensates can include TK 1000, TK 1 MM,Heatenol—Sensient Flavors, Optaheat—Symrise Flavors, Cinnamon, Capsicum,Capsaicin, Curry, FSI Flavors, Isobutavan, Nonivamide 60162807, HotactVEE, Hotact 1MM, piperine, optaheat 295 832, optaheat 204 656, optaheat200 349, and combinations thereof. Warming sensates can be present fromabout 0.005% to about 2%, in another example from about 0.01% to about1%, and in another example from about 0.1% to about 0.5%.

Non-limiting examples of tingling sensates can include sichuan pepper,hydroxy alpha sanshool, Jambu extracts, spilanthol, and combinationsthereof. In one example, tingling sensates can be present from about0.005% to about 1%, in another example from about 0.01% to about 0.5%,and another example from about 0.015% to about 0.3%.

In addition to comprising an anethole analog, the composition cancomprise additional flavoring ingredients. In one example, the flavoringingredient does not comprise an aldehyde. When present, flavoringingredients are generally used in the compositions at levels of fromabout 0.001% to about 8%, by weight of the composition.

Additional non-limiting examples of flavoring ingredients can includepeppermint oil, corn mint oil, spearmint oil, oil of wintergreen, clovebud oil, cassia, sage, parsley oil, marjoram, lemon, lime, orange,mango, cis-jasmone, 2,5-dimethyl-4-hydroxy-3(2H)-furanone,5-ethyl-3-hydroxy-4-methyl-2(5H)-furanone, vanillin, ethyl vanillin,propenyl guaethol, heliotropine, 4-cis-heptenal, diacetyl,methyl-ρ-tert-butyl phenyl acetate, menthol, methyl salicylate, ethylsalicylate, 1-menthyl acetate, oxanone, alpha-irisone, methyl cinnamate,ethyl cinnamate, butyl cinnamate, ethyl butyrate, ethyl acetate, methylanthranilate, iso-amyl acetate, iso-amyl butyrate, allyl caproate,eugenol, eucalyptol, thymol, cinnamic alcohol, octanol, octanal,decanol, decanal, phenylethyl alcohol, benzyl alcohol, alpha-terpineol,linalool, limonene, citral, maltol, ethyl maltol, carvone, menthone,β-damascenone, ionone, gamma decalactone, gamma nonalactone, gammaundecalactone and mixtures thereof. Generally suitable flavoringingredients are those containing structural features and functionalgroups that are less prone to redox reactions. These include derivativesof flavouring ingredients that are saturated or contain stable aromaticrings or ester groups. In one example, the composition comprises fromabout 0.01% to about 1% flavoring ingredients, in another example fromabout 0.05% to about 0.5% flavoring ingredients, and in another examplefrom about 0.1% to about 0.3% flavoring ingredients.

The composition can optionally include one or more salivation agents.Non-limiting examples of salivation agents include formula (I):

wherein R₁ represents C1-C2 n-alkyl; R₂ is 2-methyl-1-propyl and R₃ ishydrogen, or R₂ and R₃ taken together is a moiety (designated by thedashed lines) having the formula —(CH₂)_(n)— wherein n is 4 or 5, andcombinations thereof.

In an embodiment, the salivating agent comprises a material wherein R₂is 2-methyl-1-propyl and R₃ is hydrogen, in another embodiment thesalivating agent comprises a material wherein R₁ is C1 n-alkyl, R₂ is2-methyl-1-propyl and R₃ is hydrogen. In another embodiment, thesalivating agent comprises trans-pellitorin, a chemical having astructure according to formula (II):

In another embodiment, the salivation agent can include sodiumbicarbonate, sodium chloride, trans-pellitorin, and combinationsthereof. In one example, salivation agents can be present from about0.05% to about 2%, in another embodiment from about 0.1% to about 1%,and in another example from about 0.25%% to about 0.75%.

The liquid composition can be any color. Non-limiting examples of colorscan include red, green, amber, orange, yellow, blue, pink, violet,turquoise, and combinations thereof. In one example, the composition isgreen. In another example, the liquid composition is clear.

The composition can also comprise a dye that provides the color.Non-limiting examples dyes that may be used in the present inventioninclude FD&C blue #1, FD&C blue #2, D&C blue #4, D&C blue #9, FD&C green#3, D&C green #5, D&C green #6, D&C green #8, D&C orange #4, D&C orange#5, D&C orange #10, D&C orange #11, FD&C red #3, FD&C red #4, D&C red#6, D&C red #7, D&C red #17, D&C red #21, D&C red #22, D&C red #27, D&Cred #28, D&C red #30, D&C red #31, D&C red #33, D&C red #34, D&C red#36, D&C red #39, FD&C red #40, D&C violet #2, FD&C yellow #5, FD&Cyellow #6, D&C yellow #7, Ext. D&C yellow #7, D&C yellow #8, D&C yellow#10, D&C yellow #11, and combinations thereof. In one example, thecomposition comprises from about 0.001% to about 0.1% dye, in anotherexample from about 0.002% to about 0.05% dye, and in another exampleform about 0.003% to about 0.01% dye.

Accelerated Stability Test Method

Liquid medications containing PE are packaged in standard colorlesspolyethylene terephthalate (PET) bottles and placed in a controlledtemperature chamber that is set to the ICH accelerated stabilityconditions of 40° C. and 75% relative humidity. At the following settime points: 0 days (t=0), 30 days, 60 days, 90 days, and six-months, abottle is removed from the controlled temperature chamber. Immediatelyafter each bottle is removed, the Assay Method is performed to determinethe % w/w PE in the liquid medication.

Assay Method

The Assay Method is used for the determination of % w/w PE inrespiratory liquids. A Sample Preparation, as described below, isanalyzed by reverse-phase High Performance Liquid Chromatography (HPLC)that uses a C18 column with trifluoroacetic acid (TFA) and acetonitrile(ACN) mobile phases and a single point external standard forquantification. Detection is by UV absorbance at 275 nm with detectorresponse measured by peak area.

Sample Preparation (Results Reported in % w/w)

Tare an appropriate volumetric flask to provide the correct dilution tomatch the PE concentration of the prepared Working Standard, asdescribed below. Transfer a sample of liquid medication into thevolumetric flask and record the weight to the nearest 0.1 mg. Dilute theliquid medication in the volumetric flask and Q.S. to volume with waterand mix thoroughly. Filter the liquid medication and the water with theaid of a disposable syringe and a syringe filter into an injection vialand cap, to form the Sample Preparation. Record the volume (mL) andweight (g) of the Sample Preparation for use in the calculation below.

Stock Standard Preparation

Depending on the concentration of the sample at t=0 and the weight ofthe Sample Preparation, Weigh an appropriate amount of PE referencestandard obtained from the United States Pharmacopeia (USP) to thenearest 0.1 mg. The amount of PE reference standard depends on the PEconcentration at t=0 and the weight of the Sample Preparation.Quantitatively transfer the PE reference standard to an appropriatevolumetric flask. Next add Q.S. to volume with 0.1% v/v phosphoric acidsolution. Mix until the PE reference standard has dissolved, to form theStock Standard. Record the volume (mL) and the weight (g) of the StockStandard. The PE concentration in the Stock Standard should be conducivefor dilution to ensure the PE concentration of the Working Standard, asdescribed below, is within the linear range of the UV detector at thespecified wavelength found in Chromatographic Conditions.

Working Standard Solution Preparation

Dilute the Stock Standard so that it has the same PE concentration asthe Theoretical Sample Preparation at t=0. The Theoretical SamplePreparation at t=0 is the target PE concentration of the sample at t=0,however, this may not be the actual concentration because the PE couldstart to degrade instantaneously upon manufacturing and therefore it ispossible that the Theoretical Sample Preparation at t=0 could contain ahigher PE concentration than the Sample Preparation at t=0.

Pipette an appropriate volume of Stock Standard into an appropriatevolumetric flask. Add 0.1% v/v phosphoric acid to volume and mixthoroughly to form the Working Standard. Record the volume (mL) and thedilution factor for the Working Standard. The final concentration of PEin the Working Standard should be in the linear range of the UV detectorat the specified wavelength found in the chromatographic conditions.

Mobile Phase Preparation

Next, prepare the aqueous and organic mobile phase components, MobilePhase A and B, respectively. To prepare Mobile Phase A, add 1 mL of TFAper 1 L of purified water. For Mobile Phase B, use 100% ACN. MobilePhase A and B will be used to perform the reverse-phase gradientchromatography as described in USP Chapter <621> and the ChromatographicConditions described below.

Chromatographic Conditions

The Waters XBridge™ reverse-phase HPLC columns (available from WatersCorporation, Milford, Mass.) are equipped with a 4.6×150 mm column thatcontains a 3.5 μm C18 packing material. The column temperature is 40° C.with the flow rate at 1.0 mL/min and the detector wavelength is 275 nm.The sample injection volume is 10 μL. Certain conditions such as thecolumn temperature, flow rate, and mobile phase reagent ratio may bealtered or changed provided that adequate resolution and sensitivity areobtained per USP Chapter <621> and system suitability criteria, asdescribed below, are met.

The following gradient elution program in addition to other parametersfound in the Chromatography Conditions are used to analyze PE in bothWorking Standards and Sample Preparations:

Time (mins) % Mobile Phase A % Mobile Phase B 0.0 96 4 10.0 85 15 19.040 60 20.0 40 60 20.1 96 4 25.0 96 4System Suitability

For system suitability, inject 10 μL of the Working Standard andchromatograph until system suitability is achieved with five successiveinjections. The system suitability is the % RSD (Relative StandardDeviation) for the peak areas and the retention times for PE.

If the liquid composition comprises APAP and DXM, the system suitabilityis the % RSD for the peak areas and the retention times for PE andDextromethorphan HBr (DXM) should be 2.0% or less. Also the resolutionbetween PE and DXM should be 2.0 or greater and the peak tailing for PEshould be 2.5 or less. Peak retention order is PE followed by APAP, thenDXM.

Next, inject 10 μL of the Sample Preparation and chromatograph and theninject 10 μL of the Working Standard, this is the bracket standard.

Then, inject 10 μL of the Sample Preparation and chromatograph. Repeatthis step up with up to six samples before injecting 10 μL of theWorking Standard.

CalculationsPE(% w/w)=(W _(S) /V _(F1))*(P/100)*(DF)*(A ₂ /A ₁)*(V _(F2) /WP)*(100)

Where W_(S) in the weight of the Stock Standard (g), V_(F1) is thevolume of the Stock Standard (mL), P is the purity of the USP PEreference standard in % from the USP Certificate of Analysis, DF is thedilution factor of the Working Standard, A₂ is the chromatographicresponse of the Sample Preparation in peak area units, A₁ is thechromatographic response of the Working Standard in peak area unitsaveraged from all Working Standards tested, which include systemsuitability and all bracket standards. V_(F2) is the volume of theSample Preparation and WP is the weight of the Sample Preparation.Chromatographic response of PE in peak area units is determined byintegrating the PE peak with Empower 3 Chromatography Data Software(available from Waters, Corporation, Milford, Mass.).

Statistical Evaluation of PE Assay Data

A zero-order kinetic model is fit to the data using the % w/w PE valuesdetermined from the above calculation. This model can be used todetermine the rate of PE loss and standard error associated with thedataset to yield 95% confidence intervals at the study endpoint of6-months.

AFRICA Stability Test Method

The AFRICA Stability Test Method is performed the same as theAccelerated Stability Test Method described herein except the StabilityConditions and the Stability Predictions are different and are performedas described below.

Stability Conditions

Liquid medication samples containing PE were forcibly degraded in flowusing an Automated Flow Reaction and Incubation Control Apparatus(AFRICA) (available from Syrris Inc., Charlestown, Mass.). This wasaccomplished using a temperature ramp ranging from 80° C. to 140° C. in20° C. increments. In another example, the temperature range can beramped in any suitable increments, for instance 10° C. increments, Foreach temperature, samples were stressed under pressure (6-7 bar) for 20minutes prior to sampling for assay of PE.

Stability Prediction

Using % w/w PE values determined from HPLC assay of AFRICA samples,rates of loss (k) for each temperature were determined against % w/w PEvalues of an unexposed control sample. These losses were then convertedinto units suitable for an Arrhenius plot, where Arrhenius parameterswere derived using standard linear regression. Percent predicted PE lossfor each sample was accomplished using the calculated rate constant fromthe standard Arrhenius equation with accelerated stability conditions(40° C.) for temperature. The predicted % PE loss levels after 6-monthsof exposure are reported.

The AFRICA Stability Test Method can be used to determine thedegradation of with any drug active, including but not limited to drugactives as described herein. In another example, the AFRICA StabilityTest Method can be used to determine the degradation of oxymetazoline.

The temperature ramp can be any suitable temperature increment. In oneexample, the increment was accomplished using a temperature ramp rangingfrom 80° C. to 140° C. in 20° C. increments. In another example, thetemperature range can be ramped in any suitable increments. Non-limitingexamples of suitable ramp increments can include 5° C. increments, 10°C. increments, 15° C. increments, 20° C. increments, 25° C. increments,30° C. increments, and combinations thereof.

EXAMPLES

The following example further describes and demonstrates embodimentswithin the scope of the present invention. The examples are given solelyfor the purpose of illustration and are not to be construed aslimitations of the present invention, as many variations thereof arepossible without departing from the spirit and scope of the invention.All exemplified amounts are concentrations by weight of the totalcomposition, i.e., w/w percentages, unless otherwise specified.

The following compositions can be prepared in accordance with thepresent invention:

1 2 3 4 5 6 7 Water Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Propylene glycol23.02 23.02 23.02 23.02 23.02 23.02 23.02 APAP 2.00 2.00 2.00 2.00 2.002.00 2.00 DXM 0.062 0.062 0.062 0.062 0.062 0.062 0.062 Doxylamine 0.0380.038 0.038 0 0 0 0 succinate PE 0.031 0.031 0.031 0.031 0.031 0.0310.031 Anise Flavoring 0.21 0 0 0 0 0 0 with trans-Anetholetrans-Anethole 0 0.013 0 0 0 0 0 Dihydroanethole 0 0 0 0.001 0.015 0.210.00025 Xanthan gum 0.15 0.15 0.15 0.15 0.15 0.15 0.15 Sodium benzoate0.10 0.10 0.10 0.10 0.10 0.10 0.10 Sodium citrate 0.20 0.20 0.20 0.200.20 0.20 0.20 dihydrate Citric acid 0.22 0.22 0.22 0.22 0.22 0.22 0.22Sodium saccharin 0.13 0.13 0.13 0 0 0 0.13 Acesulfame 0.080 0.080 0.0800 0 0 0 Potassium Sodium chloride 0.50 0.50 0.50 0.50 0.50 0.50 0.50 Dye0.0043 0.0043 0.0043 0.0043 0.0043 0.0043 0.0043 Glycerin (96%) 8.008.00 8.00 8.00 8.00 8.00 8.00 Sorbitol (70%) 13.15 13.15 13.15 13.1513.15 13.15 13.15 Example No. 8 9 10 11 12 13 14 Water Q.S. Q.S. Q.S.Q.S. Q.S. Q.S. Q.S. Propylene glycol 23.02 23.02 23.02 23.02 23.02 23.0223.02 APAP 2.00 2.00 2.00 2.00 2.00 2.00 2.00 DXM 0.062 0.062 0.0620.062 0.062 0.062 0.062 Doxylamine 0 0 0 0 0 0.038 0.038 succinate PE0.031 0.031 0.031 0.031 0.031 0.031 0.031 Anise Flavoring 0 0 0.055 0.110.21 0 0 with trans-Anethole Dihydroanethole 0.00025 0.00025 0 0 00.00025 0.00025 Xanthan gum 0.075 0 0.15 0.15 0.15 0 0 95% Ethanol (1900 0 0 0 0 0 7.25 Proof) Sodium benzoate 0.10 0.10 0.10 0.10 0.10 0.100.10 Sodium citrate 0.20 0.20 0.20 0.20 0.20 0.20 0.20 dihydrate Citricacid 0.22 0.22 0.22 0.22 0.22 0.22 0.22 Sodium saccharin 0.13 0.13 0.130.13 0.13 0.13 0.10 Acesulfame 0 0 0 0 0 Potassium Sodium chloride 0.500.50 0.50 0.50 0.50 0.50 0.50 Dye 0.0043 0.0043 0.0043 0.0043 0.00430.0043 0.0043 Glycerin (96%) 8.00 8.00 8.00 8.00 8.00 8.00 8.00 Sorbitol(70%) 13.15 13.15 13.15 13.15 13.15 13.15 13.15

Examples 1-14 were made according to the following procedure. DXM, APAP,and doxylamine succinate, if present, are added to propylene glycol bymixing at an appropriate speed for at least five minutes, if the activesare not dissolved after five minutes then the solution can be warmedslightly and stirred until the actives dissolve. An appropriate mixingspeed means that the solution is mixed quickly but it does not splashout of the container. Next the flavor, which includes anise flavoring,trans-anethole, or dihydroanethole, is added to the solution and mixedfor at least five minutes or until dispersed, whichever is later. Then,if alcohol is present, it is added as a solvent to form the glycolpremix. If alcohol is not present, xanthan gum can be added to thesolution and mixed, for no less than five minutes, until dispersed, toform the glycol premix.

Next, the glycol premix is added to the water. Then, the followingcomponents are added to the solution in the following order: thebuffers, which include citric acid and sodium citrate, sodium benzoate,dye, sodium chloride, PE, and the sweeteners, which include sodiumsaccharin, acesulfame potassium, glycerin, and sorbitol. Each componentis added and incorporated into the solution before the next component isadded. The solution is mixed until all of the ingredients are dissolvedand the solution is homogenous.

The dimensions and values disclosed herein are not to be understood asbeing strictly limited to the exact numerical values recited. Instead,unless otherwise specified, each such dimension is intended to mean boththe recited value and a functionally equivalent range surrounding thatvalue. For example, a dimension disclosed as “40 mm” is intended to mean“about 40 mm.”

Every document cited herein, including any cross referenced or relatedpatent or application, is hereby incorporated herein by reference in itsentirety unless expressly excluded or otherwise limited. The citation ofany document is not an admission that it is prior art with respect toany invention disclosed or claimed herein or that it alone, or in anycombination with any other reference or references, teaches, suggests ordiscloses any such invention. Further, to the extent that any meaning ordefinition of a term in this document conflicts with any meaning ordefinition of the same term in a document incorporated by reference, themeaning or definition assigned to that term in this document shallgovern.

While particular embodiments of the present invention have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the invention. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this invention.

What is claimed is:
 1. A liquid medication comprising: a. phenylephrinehydrochloride; and b. an analog of trans-anethole that is substantiallyfree of aldehyde groups.
 2. The liquid medication of claim 1 comprisingfrom about 0.01% to about 0.1% phenylephrine hydrochloride.
 3. Theliquid medication of claim 1 comprising from about 1 ppm to about 20 ppmanalog of trans-anethole.
 4. The liquid medication of claim 1 whereinthe analog of trans-anethole is 1-methoxy-4-n-propylbenzene.
 5. Theliquid medication of claim 4 comprising 1 ppm to 10 ppm1-methoxy-4-n-propylbenzene.
 6. The liquid medication of claim 1 furthercomprising a pain reliever selected from the group consisting ofacetaminophen, ibuprofen, and combinations thereof.
 7. The liquidmedication of claim 6 wherein the pain reliever is acetaminophen.
 8. Theliquid medication of claim 1 further comprising dextromethorphan.
 9. Theliquid medication of claim 8 further comprising doxylamine succinate.10. The liquid medication of claim 1 further comprising from about 3% toabout 15% ethanol.
 11. The liquid medication of claim 1 wherein themedication has a pH of about 2 to about
 6. 12. The liquid medication ofclaim 1 wherein the liquid medication has a mean loss of phenylephrineof less than about 6% within a 95% confidence interval.
 13. The liquidmedication of claim 1 further comprising a synthetic sweetener selectedfrom the group consisting of sodium saccharin, acesulfame potassium,sucralose, aspartame, monoammonium glycyrrhizinate, neohesperidindihydrochalcone, thaumatin, neotame, cyclamates, and mixtures thereof.14. The liquid medication of claim 1 further comprising a sugar alcoholselected from the group consisting of xylitol, sorbitol, mannitol,maltitol, lactitol, isomalt, erthritol, glycerin, and combinationsthereof.
 15. A liquid medication comprising: a. phenylephrinehydrochloride; b. dextromethorphan hydrobromide; c. acetaminophen; andd. an analog of trans-anethole that is substantially free of aldehydegroups.
 16. The liquid medication of claim 15 wherein the analog oftrans-anethole is 1-methoxy-4-n-propylbenzene.
 17. The liquid medicationof claim 16 further comprising from about 10% to about 35% propyleneglycol.
 18. The liquid medication of claim 17 further comprising apreservative selected from the group consisting of benzalkoniumchloride, ethylenediaminetetraacetic acid, benzyl alcohol, potassiumsorbate, parabens, benzoic acid, sodium benzoate, and mixtures thereof.19. The liquid medication of claim 18 further comprising a syntheticsweetener selected from the group consisting of sodium saccharin,acesulfame potassium, sucralose, aspartame, monoammoniumglycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotame,cyclamates, and mixtures thereof.
 20. The liquid medication of claim 15further comprising diphenhydramine.